2025 was a consequential year for cholangitis, marked by both renewed momentum and sobering recalibration across primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Advances in regulatory alignment, symptom-focused therapies, and long-term disease modification highlighted a field increasingly centered on patient-relevant outcomes, even as setbacks underscored the complexity of treating these rare cholestatic diseases.

Regulatory developments set much of the year’s tone. The US Food and Drug Administration (FDA)’s orphan drug designation for CNP-104 and alignment on a registrational phase 3 pathway for nebokitug represented rare progress toward viable approval routes in PBC and PSC, conditions long hindered by the absence of validated surrogate endpoints. In contrast, the voluntary withdrawal of obeticholic acid from the US market reinforced ongoing safety and efficacy challenges, reshaping expectations for established therapies and sharpening focus on next-generation agents.

Clinical data throughout 2025 emphasized symptomatic improvement alongside biochemical and antifibrotic signals. Multiple late-phase and long-term studies demonstrated meaningful reductions in pruritus, fatigue, and cholestatic biomarkers with agents such as elafibranor, linerixibat, volixibat, and seladelpar, reflecting a broader shift toward holistic disease management. Together, these developments positioned 2025 as a pivotal year helping to clear the path forward for cholangitis research while raising the bar for future therapies in PBC and PSC.

FDA News

FDA Grants Orphan Drug Designation to CNP-104 for Primary Biliary Cholangitis

On January 8, 2025, the FDA granted Orphan Drug Designation to CNP-104 for the treatment of PBC following the presentation of positive topline data from the phase 2a clinical trial of CNP-104 in PBC at the American Association for the Study of Liver Diseases’ The Liver Meeting in 2024.

Nebokitug (CM-101) Gets FDA Runway for PSC Approval

On February 19, 2025, Chemomab Therapeutics announced the successful completion of an end-of-phase 2 meeting with the FDA as well as alignment with the agency on the design of a single phase 3 registration study for nebokitug (CM-101) for the treatment of PSC.

“Until now, the pathway to drug approval in PSC has been problematic due to the lack of validated surrogate endpoints and clarity around primary efficacy endpoints for PSC registration trials. This has been a major hindrance to the development of effective therapies for PSC,” Christopher Bowlus, MD, the Lena Valente Professor and Chief of the Division of Gastroenterology and Hepatology at the University of California Davis School of Medicine, commented. “The agreed composite endpoint approach for the nebokitug trial enhances our chances of efficiently and accurately identifying the potential clinical benefits of this promising new drug.

Intercept Voluntarily Withdraws Obeticholic Acid (Ocaliva) for PBC From US Market

On September 11, 2025, Intercept Pharmaceuticals announced its decision to voluntarily withdraw obeticholic acid (Ocaliva) from the US market for the treatment of PBC following a request from the FDA, The Agency additionally placed a clinical hold on all Intercept clinical trials conducted under a US IND involving obeticholic acid.

Trial Updates and New Guidelines

Volixibat Improves Fatigue and Sleep in Patients With Primary Biliary Cholangitis

Findings from the 28-week randomized, multicenter, double-blind, placebo-controlled phase 2b VANTAGE study shed light on the impact of treatment with volixibat on sleep and fatigue in patients PBC, building upon the agent’s known impact on pruritus in this patient population.

Phase 2 ELMWOOD Data for Elafibranor in PSC, with Cynthia Levy, MD

Data from the phase 2 ELMWOOD study of elafibranor in patients with PSC shed light on the peroxisome proliferator-activated receptor (PPAR) agonist’s safety and tolerability in this patient population. Study findings were presented at the European Association for the Study of the Liver (EASL) congress and suggest elafibranor may be a potential treatment option for PSC, a chronic liver disease for which none currently exist.

Long-Term Elafibranor Treatment Leads to Biochemical, Symptomatic Improvements in PBC

Data from the ongoing ELATIVE open-label extension study highlight elafibranor’s long-term ability to improve liver health biomarkers, stabilize fibrosis, and reduce fatigue and itching symptoms in patients with PBC. Findings presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 demonstrated rapid, sustained, and reproducible responses in clinically relevant biomarkers of cholestasis and fibrosis as well as positive effects on cholestasis, sustained improvement in pruritus and fatigue, stabilization of markers of fibrosis.

GLISTEN: Linerixibat Improves Biomarkers and Itch in Patients With PBC, With Andreas Kremer, MD, PhD, MHBA

Results from GLISTEN, the largest investigational study of pruritus in PBC, highlight the effects of linerixibat on pharmacodynamic biomarkers of bile acid metabolism and mediators of cholestatic pruritus in this patient population Findings hold important implications for PBC management, showing increases in serum C4 and reductions in FGF-19, total serum bile acids, autotaxin, and interleukin-31, validating the biologic mechanism of linerixibat and its impact on cholestatic pruritus in PBC.

Seladelpar’s Long-Term Benefit for Pruritus in PBC, With Gideon Hirschfield, FRCP, PhD

At the AASLD The Liver Meeting 2025, Gideon Hirschfield, FRCP, PhD, director of The Autoimmune and Rare Liver Disease Programme and the Lily and Terry Horner Chair in Autoimmune Liver Disease Research in the division of gastroenterology and hepatology at Toronto General Hospital, presented long-term pruritus outcomes from the RESPONSE study of seladelpar in adults with PBC and interim results from its ongoing open-label extension study, ASSURE, demonstrating sustained, clinically meaningful improvement in itch among patients with moderate to severe pruritus.

Feature Content/Podcasts

Liver Lineup: Innovations in Cholestatic Disease Management, With Kris Kowdley, MD

In this episode of Liver Lineup: Updates & Unfiltered Insights, Nancy Reau, MD, sits down with Kris Kowdley, MD, to discuss evolving approaches in cholestatic liver disease, with a particular focus on PBC diagnosis and shifting treatment goals.

2025 in Hepatology: New MASLD Therapies, HBV Updates, and More

As part of HCPLive’s This Year in Medicine series, the editorial team of HCPLive Hepatology invited 7 leading experts to weigh in on the most important advances of 2025. Their responses ranged from the long-awaited arrival of effective pharmacologic treatments for MASLD/MASH to renewed innovation in viral hepatitis, cholestatic liver diseases, portal hypertension, and alcohol-associated liver disease, as well as emerging noninvasive diagnostics, evolving disease definitions, AI-enabled pathology, and increasingly patient-centered care models.

Liver Lineup: Advances in MASH, PSC, and PBC Care at EASL 2025

In this episode of Liver Lineup: Updates & Unfiltered Insights, Nancy Reau, MD, and Kimberly Brown, MD, discuss a trio of notable abstracts presented at the 2025 EASL Congress, including the LITMUS Study, norursodeoxycholic acid in PSC, and the GLOBE Score for PBC.